This application addresses broad Challenge Area (11) Regenerative Medicine and specific Challenge Topic, 11-HL-101: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Derivation of patient-specific induced pluripotent stem (iPS) cells opens a new avenue for the future applications of regenerative medicine. However, it is critical to validate iPS cells'in vivo behavior and fate after autologous transplantation in pre-clinical large animal models before their safe clinical application becomes possible. The pig heart is anatomically and physiologically more similar than small animal models to human and therefore can serve as an excellent model for evaluating and validating individual-specific iPS cell-based therapies. In this NIH Challenge Grant proposal, we propose to generate porcine iPS cells from pig adipose stromal cells with a novel non-viral minicircle vector. Cardiomyocytes that are derived from individual-specific porcine iPS cells will undergo autologous cardiac transplantation. The in vivo survival, proliferation, differentiation, and integration of transplanted individual-specific cardiomyocytes will then be evaluated with novel molecular imaging techniques. Together, porcine iPS cells, iPS derivatives, and the autologous transplantation model should provide valuable information for future clinical translation of human patient-specific iPS cell therapies. PUBLIC HEALTH RELEVANCE: The combination of individual-specific porcine iPS cells and the large animal pig model creates an excellent pre-clinical model for evaluating and validating individual-specific iPS cell-based therapies in humans. We propose to generate porcine iPS cells and obtain iPS cell-derived heart muscle cells to assess the in vivo therapeutic effect of autologous transplantation using novel molecular imaging techniques. If successful, this study will provide valuable pre-clinical information for future clinical trials on patient-specific regenerative therapies for such diseases such as congestive heart failure and congenital heart conditions, etc.